Cancer is characterized primarily by an increase in the number of abnormal cells derived from a given normal tissue, invasion of adjacent tissues by these abnormal cells, or lymphatic or blood-borne spread of malignant cells to regional lymph nodes and to distant sites (metastasis). Clinical data and molecular biologic studies indicate that cancer is a multistep process that begins with minor preneoplastic changes, which may under certain conditions progress to neoplasia. The neoplastic lesion may evolve clonally and develop an increasing capacity for invasion, growth, metastasis, and heterogeneity, especially under conditions in which the neoplastic cells escape the host's immune surveillance. Roitt, I., Brostoff, J. and Kale, D., Immunology, 17.1-17.12 (3rd ed., Mosby, St. Louis, Mo., 1993).
There is an enormous variety of cancers which are described in detail in the medical literature. Examples includes cancer of the blood, lung, colon, rectum, prostate, breast, brain, and intestine. The various forms of the cancers such as lymphomas are described in U.S. provisional application No. 60/380,842, filed May 17, 2002, the entireties of which are incorporated herein by reference (see, e.g., Section 2.2. Types of Cancers).
Many types of cancers are associated with new blood vessel formation, a process known as angiogenesis. Several of the mechanisms involved in tumor induced angiogenesis have been elucidated. The most direct of these mechanisms is the secretion by the tumor cells of cytokines with angiogenic properties. Examples of these cytokines include acidic and basic fibroblastic growth factor (“a,b FGF”), angiogenin, vascular endothelial growth factor (“VEGF”), and TNF-α. Alternatively, tumor cells can release angiogenic peptides through the production of proteases and the subsequent breakdown of the extracellular matrix where some cytokines are stored (e.g., bFGF). Angiogenesis can also be induced indirectly through the recruitment of inflammatory cells (particularly macrophages) and their subsequent release of angiogenic cytokines (e.g., TNF-α, bFGF).
Accordingly, compounds that can control angiogenesis or inhibit the production of certain cytokines, including TNF-α, may be useful in the treatment and prevention of various cancerous diseases and conditions.
Lymphoma is a heterogenous group of neoplasms arising in the reticuloendothelial and lymphatic systems. The Merck Manual, 955 (17th ed. 1999). Non-Hodgkin's lymphoma (“NHL”) refers to malignant monoclonal proliferation of lymphoid cells in the immune system, including lymph nodes, bone marrow, spleen, liver and gastrointestinal (“GI”) tract. The Merck Manual, at 958.
Mantle cell lymphoma (“MCL”) is a distinct entity among the non-Hodgkin's lymphomas. Drach J.; et al., Expert Review of Anticancer Therapy, 2005, 5(3), pp. 477-485. In the International Lymphoma Classification Project, MCL accounted for 8% of all non-Hodgkin lymphomas. MCL is recognized in the Revised European-American Lymphoma and World Health Organization classifications as a distinct clinicopathologic entity. MCL was not recognized by previous lymphoma classification schemes; and it was frequently categorized as diffuse small-cleaved cell lymphoma by the International Working Formulation or centrocytic lymphoma by the Kiel classification. The Merck Manual, at 958-959.
MCL is a lymphoproliferative disorder derived from a subset of naive pregerminal center cells localized in primary follicles or in the mantle region of secondary follicles. MCL is characterized by a specific chromosomal translocation, the t(11; 14)(q13;q32). Drach J.; et al., Expert Review of Anticancer Therapy, 2005, 5(3), pp. 477-485. This translocation involves the immunoglobulin heavy-chain gene on chromosome 14 and the BCL1 locus on chromosome 11. Drach J.; et al., p 477. The molecular consequence of translocation is overexpression of the protein cyclin D1 (coded by the PRAD1 gene located close to the breakpoint). Id. Cyclin D1 plays a key role in cell cycle regulation and progression of cells from G1 phase to S phase by activation of cyclin-dependent kinases. Id.
NHL has been associated with viral infection (Ebstein-Barr virus, HIV, human T-lymphotropic virus type 1, human herpesvirus 6), environmental factors (pesticides, hair dyes), and primary and secondary immunodeficiency. No causative factor has been identified for MCL or for most patients with NHL of other types. MCL has poor clinical outcome and is an incurable lymphoma with limited therapeutic options for patients with relapsed or refractory disease. Drach J.; et al., p. 477.
Primary central nervous system lymphoma (“PCNSL”) is most frequently a diffuse large B cell lymphoma (“DLBCL”) confined to the central nervous system (“CNS”) and carries a poor prognosis. Ferreri, A. J., Blood, 2011, 118, pp. 510-522. CNS tumor microenvironment plays an important role in the biology of CNS lymphoma. The standard therapy consists of high-dose methotrexate and high-dose ara-c with or without radiation. Although there has been an improvement in the survival due to these treatments, the prognosis of CNS lymphoma remains poor compared to systemic DLBCL. Id. Current therapeutic agents target lymphoma cells and have no significant impact on the tumor microenvironment. The blood brain barrier is a major obstacle for effective treatment of CNS lymphoma. Therefore, a tremendous demand exists for new methods, therapeutic agents, and compositions with better efficacy, excellent CNS penetration, and impact on the tumor microenvironment as well as lymphoma cells.